1463P IL-6 triggers chemoimmunotherapy resistance by creating immunosuppressive tumor microenvironment in non-small cell lung cancer

Chemotherapy in combination with anti-PD-1/PD-L1 antibodies (chemoimmunotherapy) has become the standard treatment for advanced non-small cell lung cancer (NSCLC). Our previous studies highlighted that low baseline concentrations of IL-6 in plasma specimens or tumor tissues responded better to anti-PD-1/PD-L1 immunotherapy alone. However, the role of baseline IL-6 levels in predicting responses to chemoimmunotherapy and the development of resistance to chemoimmunotherapy has not been fully understood yet. To confirm the predictive value of IL-6 in the baseline plasma, we conducted an enzyme-linked immunosorbent assay (ELISA) in a group of 123 advanced NSCLC patients who received chemoimmunotherapy. Next, we evaluated the role of IL-6 in chemoimmunotherapy resistance and the underlying mechanisms in mouse models of both lung adenocarcinoma and lung squamous cell carcinoma. Based on our cohort of 123 NSCLC patients, we found that patients with progressive disease had a higher baseline level of IL-6 in their plasma. Additionally, the potential predictive value of the baseline level of IL-6 in plasma samples for responses was confirmed with area under curve (AUC) up to 0.677. Patients with a low baseline concentration of IL-6 also had a longer progression-free survival and overall survival, with a cut-off value of 7.002 obtained from receiver operating characteristic curve (ROC). Meanwhile, univariate and multivariate Cox regression analyses revealed that baseline IL-6 level in plasma samples was an independent prognostic predictor. Further experiments in mouse models showed that overexpression of IL-6 weakened the anti-tumor effects of immunotherapy in combination with chemotherapy. Immunohistochemical studies also revealed that CD8+ T cells decreased while M2 macrophages, regulating T cells, and myeloid-derived suppressor cells infiltration increased in the IL-6 overexpressing group. Our study highlights the potential of baseline IL-6 levels as a useful predictive biomarker for chemoimmunotherapy in NSCLC. IL-6 promotes an immunosuppressive tumor microenvironment, suggesting that targeting IL-6 could be a promising approach for cancer treatment.